CN1490305A - Preparation of 5-aminol evulinic acid and its derivatives - Google Patents
Preparation of 5-aminol evulinic acid and its derivatives Download PDFInfo
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- CN1490305A CN1490305A CNA021462496A CN02146249A CN1490305A CN 1490305 A CN1490305 A CN 1490305A CN A021462496 A CNA021462496 A CN A021462496A CN 02146249 A CN02146249 A CN 02146249A CN 1490305 A CN1490305 A CN 1490305A
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Abstract
A process for preparing 5-aminoketone pentanoic acid and its derivative includes such steps as bromonating the raw compound, direct Gaiboruier reacting to obtain N-alkylphaloylimine, purifying and hydrolyzing. Its product has high purity.
Description
The present invention relates to the new preparation method of 5-aminolevulinic acid (ALA) and derivative thereof.
Photochemotherapy, both photodynamic therapy (PDT) was a kind of technology, especially cancer or lesion precancerous that various skins or other epithelium or mucous membrane are unusual or lack of proper care that be used for the treatment of of appearance recently, and some non-malignant lesions.Photochemotherapy relates to photosensitization (photochemical therapy) agent and is applied to health and is attacked the position, is exposed to photosensitization light then and is converted into the cell toxicant form with the activation light sensitiser and with them, kills thus and is attacked cell or reduce its hyperplasia potential.The aminoguanidine hydrochloride levulinic acid is a photodynamic therapy medicine of new generation, is the hydrochloride of Pp precursor 5-aminolevulinic acid (ALA), is used for actinic keratosis (Actinic Keratoses, treatment AK) clinically.
Have the 5-aminolevulinic acid of document and patent report and the preparation method of derivative thereof to have following several:
1. be raw material with the levulinic acid, prepare aminoguanidine hydrochloride levulinic acid (Synthetic Communications, 24 (18), 2557 (1994)) through bromination, azide, hydrogenolysis.
2. be raw material with the Padil, prepare aminoguanidine hydrochloride levulinic acid (Journal of Chemical Society, 1820 (1954)) through imidization, chloride, condensation, decarboxylation, hydrolysis reaction.
3. be starting raw material with the Succinic anhydried, prepare aminoguanidine hydrochloride levulinic acid (Tetrahedron Letters, 25 (28), 2977 (1984)) through mono-esterification, chloride, cyaniding, reduction, hydrolysis reaction.
4. be starting raw material with the furylamine, prepare aminoguanidine hydrochloride levulinic acid (EP607,952) through imidization, photoxidation, reduction, hydrolysis reaction.：
5. be starting raw material with the furylamine, prepare aminoguanidine hydrochloride levulinic acid (EP483,714) through reduction, imidization, ruthenium catalyzed oxidation, hydrolysis reaction.
6. be starting raw material with the epoxy chloropropane, prepare aminoguanidine hydrochloride levulinic acid (Journal of OrganicChemistry, 24,556 (1959)) through the reaction of lid Bloomsbury that, bromination, oxidation, condensation, hydrolysis, decarboxylation, hydrolysis reaction.
7. be raw material with the levulinic acid, prepare aminoguanidine hydrochloride levulinic acid (Canadian Journal of Chemistry, 52,3257 (1974) through bromination, the reaction of lid Bloomsbury that, hydrolysis reaction; Bulletin de Societe Chimique de France, 1750 (1956)).
More than in seven routes, route 1 raw material is simple and easy to, but uses sodiumazide, industrial production is dangerous; Route 2 reactions steps are long, and part material is not easy to obtain; Route 3 raw materials are simple, and step is longer, and use the highly toxic substance prussiate, and the big operation of pollution is dangerous; Route 4 method novelties, but photooxidation reaction is difficult for industrialization; Route 5 adopts the noble ruthenium catalyzed oxidation and should go on foot reaction yield low (37%), and is also inadvisable; Route 6 reaction schemes are long, and industrial prospect is poor; Route 7 method therefor steps are short, and raw material is easy to get inexpensive, therefore the most suitable suitability for industrialized production.But use the technical barrier that also there is suitability for industrialized production in route 7 methods: in the levulinic acid bromination process, except that 5-bromine substitution product, the ratio of main by product 3-bromine substitution product is also very high, this isomeric by product is difficult to control by the control reaction conditions, and main method by purifies and separates.In the technology in the past, mainly be to separate by the method for column chromatography or high vacuum rectification, and realize that this type of technological operation cost is all higher, and because bromo-derivative has bigger pungency to human body, above-mentioned sepn process all can cause in various degree physical impairment to operator.
Based on above reason, we are devoted to seek a kind of new purification process to address the above problem.We find that therefore bromo-derivative can only separate with the mode of column chromatography or rectification under vacuum owing to be oily matter, but through after cover Bloomsbury that prepared in reaction and becoming the N-alkyl phthalic imide, product is a solid.Because therefore the N-alkyl phthalic imide of different the position of substitution different solubleness in a certain solvent can separate product with simple recrystallization method.This has directly facilitated generation of the present invention.
Method of the present invention has following advantage:
1. do not need in this law the bromination after product is separated, reaction mixture is directly become the N-alkyl phthalic imide through your prepared in reaction of lid Bloomsbury, method by recrystallization can reach the purifies and separates effect then, has avoided infringement to health thereby reduced the operator simultaneously with the chance of bromide contact.
2. will be hydrolyzed according to the N-alkyl phthalic imide behind this law purifying, can obtain highly purified 5-aminolevulinic acid or derivatives thereof.
Detailed Description Of The Invention
The present invention relates to the preparation method of 5-aminolevulinic acid and derivative thereof.
Preparation method of the present invention is divided into two stages: in the stage one, use known method, with the compound of formula (I)
In the formula, R represents C
1～C
4Alkyl after bromination, carry out simple aftertreatment, without purifies and separates, directly become the N-alkyl phthalic imide through your prepared in reaction of lid Bloomsbury; In the stage two, the N-alkyl phthalic imide with stage one preparation in suitable solvent, as alcohols, aromatic hydrocarbons, ketone etc., carries out recrystallization; Stage three, with the N-alkyl phthalic imide of stage two preparations, use known method, as in acid solution or alkali lye, be hydrolyzed, finally obtain highly purified 5-aminolevulinic acid or derivatives thereof.
Following embodiment just is used to illustrate the present invention, and unrestricted the present invention.
Embodiment 1
In the 2L there-necked flask, add levulinic acid 116g (1.0mol), methyl alcohol 1200ml stirs dropping liquid bromine 180g (1.0mol) down.Dropwise, heating refluxes, and cooling concentrates.In enriched material, add entry and ethyl acetate, the sodium bicarbonate neutralization.Tell organic layer, the water layer ethyl acetate extraction.Merge organic phase, anhydrous sodium sulfate drying filters, and concentrates.In resistates, add N, dinethylformamide 700ml, potassium phthalimide 181g (1.0mol), reacting by heating.Cooling is filtered.In the filtrate impouring frozen water, separate out solid.Filter, drying gets light yellow solid 165g.
Embodiment 2
In the 2L there-necked flask, add phthalic imidine methyl ester levulinate 165g according to embodiment 1 preparation, dehydrated alcohol 1200ml, gac 20g refluxed after 30 minutes, suction filtration while hot, solid is separated out in the placement of filtrate room temperature.Filter, drying gets off-white color solid 67.7g, yield 26% (calculating with levulinic acid), fusing point: 89.4-91.0 ℃.
1H-NMR(300M，CDCl
3)：δ：2.65(2H，t，-CH
2-)，2.83(2H，t，-CH
2-)，3.67(3H，s，-OCH
3)，4.53(2H，s，Ar-CH
2-CO-)，7.87(2H，m，Ar-H)，7.74(2H，m，Ar-H).
Embodiment 3
In the there-necked flask of 1L, add 5-phthalic imidine methyl ester levulinate 53g according to embodiment 2 preparations, 7N hydrochloric acid 530ml, reflux reacts complete to hydrolysis.Cooling is filtered.Filtrate is used dichloromethane extraction, concentrates water, gets the off-white color solid.Recrystallization in the mixed solvent of water-acetone gets the 9.0g white crystal, yield 27%, mp:148.6-150.2 ℃.
1H-NMR(300M，D
2O)：δ：2.52(2H，t，-CH
2-)，2.71(2H，t，-CH
2-)，3.94(2H，s，-CH
2-).
Claims (5)
1.5-the new method of aminolevulinic acid and derivative thereof, this method comprise the compound with formula (I)
In the formula, R represents C
1～C
4Alkyl after bromination, without purifies and separates, directly through your reaction of lid Bloomsbury, preparation N-alkyl phthalic imide.Behind the purifying, prepare highly purified 5-aminolevulinic acid and derivative thereof through hydrolysis reaction.
2. the described method of claim 1, its Chinese style (I) compound is a levulinic acid.
3. the described method of claim 2, your product of reaction of its middle cover Bloomsbury is a 5-phthalic imidine methyl ester levulinate.
4. the method for claim 3, wherein the purification process of 5-phthalic imidine methyl ester levulinate is a recrystallization.
5. the method for claim 3, wherein the product for preparing after the hydrolysis of 5-phthalic imidine methyl ester levulinate is the aminoguanidine hydrochloride levulinic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021462496A CN1490305A (en) | 2002-10-17 | 2002-10-17 | Preparation of 5-aminol evulinic acid and its derivatives |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021462496A CN1490305A (en) | 2002-10-17 | 2002-10-17 | Preparation of 5-aminol evulinic acid and its derivatives |
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| CN1490305A true CN1490305A (en) | 2004-04-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA021462496A Pending CN1490305A (en) | 2002-10-17 | 2002-10-17 | Preparation of 5-aminol evulinic acid and its derivatives |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101052617B (en) * | 2004-11-03 | 2010-11-03 | 阿尔法合成有限公司 | Process for the preparation of alkyl 5-(dicarboximido)levulinate and alkyl 4-oxo-pentenoate |
| CN102627573A (en) * | 2012-03-30 | 2012-08-08 | 山东大学 | Synthesis method for 5-aminolevulinic acid hydrochloride |
| CN102649769A (en) * | 2011-02-25 | 2012-08-29 | 上海泺安医药技术有限公司 | New preparation process of 5-aminolevulinic acid (5-ALA) ester hydrochloride |
| CN101745102B (en) * | 2008-12-16 | 2013-08-07 | 上海复旦张江生物医药股份有限公司 | Composition of 5-aminolevulinic acid and derivative thereof as well as application thereof |
| CN104140376A (en) * | 2013-05-10 | 2014-11-12 | 王俊科 | Method for synthesizing 5-aminolaevulic acid |
-
2002
- 2002-10-17 CN CNA021462496A patent/CN1490305A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101052617B (en) * | 2004-11-03 | 2010-11-03 | 阿尔法合成有限公司 | Process for the preparation of alkyl 5-(dicarboximido)levulinate and alkyl 4-oxo-pentenoate |
| CN101745102B (en) * | 2008-12-16 | 2013-08-07 | 上海复旦张江生物医药股份有限公司 | Composition of 5-aminolevulinic acid and derivative thereof as well as application thereof |
| CN102649769A (en) * | 2011-02-25 | 2012-08-29 | 上海泺安医药技术有限公司 | New preparation process of 5-aminolevulinic acid (5-ALA) ester hydrochloride |
| CN102649769B (en) * | 2011-02-25 | 2015-12-16 | 上海泺安医药技术有限公司 | A kind of preparation technology of 5-aminolevulinic acid ester |
| CN102627573A (en) * | 2012-03-30 | 2012-08-08 | 山东大学 | Synthesis method for 5-aminolevulinic acid hydrochloride |
| CN102627573B (en) * | 2012-03-30 | 2013-09-25 | 山东大学 | Synthesis method for 5-aminolevulinic acid hydrochloride |
| CN104140376A (en) * | 2013-05-10 | 2014-11-12 | 王俊科 | Method for synthesizing 5-aminolaevulic acid |
| WO2014180175A1 (en) * | 2013-05-10 | 2014-11-13 | 甘肃祁连食用菌工程技术研究中心 | Method for synthesising 5-aminolevulinic acid |
| CN104140376B (en) * | 2013-05-10 | 2015-11-18 | 王俊科 | A kind of method of synthesizing 5-ALA |
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